Coronary Heart Disease (CHD) is one of the most common diagnoses of hospital patients in the United States, with over five million cases occurring yearly. Platelet activation plays an important role in a variety of vascular events, diseases and disorders. When trauma of the blood vessel wall occurs, a series of reactions also occur. A clot, also referred to as a thrombus, is involved in many vascular diseases including cardiovascular (e.g., heart failure) and cerebrovascular diseases (e.g., stroke). Vascular diseases that result from the activation of platelets pose serious problems to patients and the physicians who treat them. Physicians continue to search for better preventative and/or curative treatments for vascular diseases that are associated with platelet activation.
Hence, a need exists for new and improved treatment options for individuals who have vascular diseases. Additionally, a need exists for therapies which target receptors that are involved in and/or cause platelet activation.
The present invention pertains to methods of reducing the platelet activation state of an individual. The methods comprise administering to the individual an effective amount of at least one serotonin inhibitor or antagonist. In one embodiment, the serotonin inhibitor or antagonist is a selective serotonin reuptake inhibitor (SSRI) (e.g., sertraline, fluvoxamine, paroxetine, citalopram, fluoxetine, venlafaxine, mirtazapine, buspirone, trazodone, nefazadone, clomipramine, imipramine, nortriptyline, mianserine, duloxetine, dapoxetine, litoxetine, femoxetine, lofepramine, tomoxetine or metabolites thereof). The SSRI prevents the reduction of serotonin in blood of the individual. The SSRI can be administered, for example, orally, intravenously, intramuscularly, subcutaneously, parenterally, nasally, by inhalation, by implant, by injection, or by suppository. In particular, the above-mentioned SSRIs can be administered orally in an amount between about 2 mg-2500 mg/daily. Upon administration of a SSRI, the platelet activation state is reduced. The platelet activation state is assessed by measuring at least one platelet activation marker. One or more platelet activation markers is reduced by at least about 10% (e.g., by 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%), and is indicative of a reduction in the platelet activation state. Examples of platelet activation markers are: CD9, GPIb, GPIIb, GPIIIa, CDIa-IIa, P-selectin, PECAM-1, GPIIb/IIIa, vitronectin receptor, other integrins and adhesive molecules.
Another embodiment of the present invention includes methods of preventing or treating an individual at risk for one or more vascular events, diseases or disorders. These methods comprise administering to an individual an effective amount of at least one serotonin inhibitor or antagonist, wherein the platelet activation state is reduced. A SSRI such as sertraline, fluvoxamine, paroxetine, citalopram, fluoxetine, venlafaxine, mirtazapine, buspirone, trazodone, nefazadone, clomipramine, imipramine, nortriptyline, mianserine, duloxetine, dapoxetine, litoxetine, femoxetine, lofepramine, tomoxetine or metabolites thereof can be administered. Some examples of vascular events, diseases or disorders are myocardial infarction, angina, stroke, pulmonary embolism, transient ischemic attack, deep vein thrombosis, thrombotic re-occlusion subsequent to a coronary intervention procedure, heart surgery or vascular surgery, peripheral vascular thrombosis, Syndrome X, heart failure, and a disorder in which a narrowing of at least one coronary artery occurs. In one embodiment, administration of the SSRIs reduces the platelet activation state. Platelet activation is assessed with the measurement of platelet activation markers. At least one platelet activation marker (e.g., CD9, GPIb, GPIIb, GPIIIa, CDIa-IIa, P-selectin, PECAM-1, GPIIb/IIIa, vitronectin receptor, other integrins or adhesive molecules) decreases (e.g., by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%), as compared to the level of the platelet activation marker just prior to administration to an individual who has an active or elevated platelet activation state. In another embodiment, when administering a SSRI to an individual to prevent a vascular event, disease or disorder, the platelet activation state can be prevented from increasing (e.g., remain at same level or decrease), as measured by platelet activation markers. In particular, the present invention pertains to methods of treating an individual with or preventing an individual from having coronary heart disease.
The present invention also includes administration of a SSRI together with other drugs or compositions used to treat or prevent vascular events, diseases, or disorders; or other drugs used to reduce or inhibit platelet activation. Hence, another embodiment of the present invention relates to methods of preventing or treating an individual at risk for a vascular event, disease or disorder, that comprise administering to the individual an effective amount of a serotonin inhibitor or antagonist (e.g., a SSRI), and at least one other composition used for treating or preventing a vascular event, wherein the platelet activation state decreases. Examples of drugs or compositions that can be administered with a SSRI are aspirin, heparin, thienopyridines and GPIIb/IIIa inhibitors.
The methods further include inhibiting or reducing platelet activation by contacting platelets with a selective serotonin reuptake inhibitor in an amount sufficient to inhibit or reduce platelet activation. The platelet activation state is indicated by a reduction in one or more platelet activation markers (e.g., CD 9, GPIb, GPIb, GPIIIa, CDIa-IIa, P-selectin, PECAM-1, GPIIb/IIIa, vitronectin receptor, other integrins and adhesive molecules).
The present invention takes advantage of the discovery that serotonin plays a role in platelet activation. The present invention provides effective treatment options for individuals that have vascular diseases by targeting serotonin activity.